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Altered protein involved in a novel link to Alzheimer's disease

Federation of American Societies for Experimental Biology

New findings of the presence of beta amyloid in the brain of a mouse that overproduces a protein called p25 may help explain the occurrence of sporadic Alzheimer's (as opposed to the less common familial form of the disease) and also why stroke and high blood pressure increase the likelihood of developing Alzheimer's.

Dr. Li-Huei Tsai, a Howard Hughes Medical Institute investigator at Harvard Medical School, presented the latest discovery made possible by her new mouse model for Alzheimer's and other neurodegenerative diseases on June 15 at the annual meeting of the American Society for Biochemistry and Molecular Biology (ASBMB)/8th International Union of Biochemistry and Molecular Biology Conference (IUBMB) in Boston.

Working in collaboration with other labs, the Harvard/Howard Hughes research team is already testing potential compounds to halt, or even prevent, the complex cascade of events caused by the presence of p25 that lead to neurodegeneration. In addition, Dr. Tsai believes their work may suggest an intervention after stroke to lower or prevent additional risk of Alzheimer's. With Dr. Tsai's discovery of beta amyloid in the brain of her mouse model, it is now evident that the overexpression of the p25 protein induces all three pathological features of Alzheimer's disease: beta amyloid plaques (caused by increased Abeta peptides), neurofibrillary tangles caused by hyperphosphorylation of tau, and brain atrophy/loss of neurons. Only low levels of the protein P25 are found in healthy brains. However, in the brains of people with Alzheimer's, the p25 proteins are significantly increased.

P25 is actually a fragment of another protein, and can be formed when a stroke or some other unknown event causes the parent protein, p35, to break. But the newly created p25 behaves very differently from the protein from which it was carved out, says Dr. Tsai. Unlike its shorter-lived parent, p25 keeps accumulating in the brain. It causes its most severe damage indirectly, however, by the way it alters the behavior of an enzyme in the brain called Cdk5. When Cdk5 pairs with the original p35 protein, it assures that the brain's neurons remain healthy and assemble in the appropriate neuronal patterns. But when the p25 protein takes over, Cdk5 becomes overactive and actually begins killing neurons. Dr. Tsai created her unique mouse model last year by breeding mice with a gene that overproduces p25, then blocking expression of that gene with the chemical doxycycline until the mouse are mature and their brains have had a chance to develop. When the chemical is removed from the animals' diets, the p25 gene is free to act - and the damage is quick and heavy: atrophy, neuronal death, tangles, tau, and now beta amyloid. Dr. Tsai says the questions now focus on the mechanism that causes p35 to get turned into p25. Understanding that - and having this mouse model makes the chances much more likely - would allow scientists to find a way to prevent p25 from ever having a chance to cause such devastating neurodegeneration.


Co-authors of the ASBMB paper are Jonathan Cruz and Dohoon Kim, both of the Harvard Medical School Department of Pathology. Funding for the study came from the Alzheimer's Research Consortium. With more than 11,900 members, the American Society of Biochemistry and Molecular Biology is a nonprofit scientific and education organization dedicated to promoting understanding of the molecular nature of life processes.

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